Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.
Lupus nephritis (LN) is a heterogeneous complication of systemic lupus erythematosus that remains a considerable unmet medical need.
Genetic and epigenetic factors confer risks of LN incidence and progression.
Single-cell analyses and enhanced microscopic analyses of renal tissues are yielding new information about LN pathogenesis and the progression of chronic kidney disease.
Improvements in risk assessment using genetic or transcriptomic biomarkers could enable the design of clinical trials to prevent LN onset and progression.
Trials might need to be tailored according to the genetic profile of the patient, a biomarker-based evaluation of their renal tissue and/or the mechanism of action of each new drug.
Developments in the understanding of tubulointerstitial injury and repair are yielding new strategies for preserving renal function and preventing fibrosis.
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Almaani, S., Meara, A. & Rovin, B. H. Update on lupus nephritis. Clin. J. Am. Soc. Nephrol. 12, 825–835 (2017).
Brunner, H. I., Gladman, D. D., Ibanez, D., Urowitz, M. D. & Silverman, E. D. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 58, 556–562 (2008).
Hoover, P. J. & Costenbader, K. H. Insights into the epidemiology and management of lupus nephritis from the US rheumatologist’s perspective. Kidney Int. 90, 487–492 (2016).
Boumpas, D. T., Bertsias, G. K. & Fanouriakis, A. 2008–2018: a decade of recommendations for systemic lupus erythematosus. Ann. Rheum. Dis. 77, 1547–1548 (2018).
Wilhelmus, S. et al. Lupus nephritis management guidelines compared. Nephrol. Dial. Transpl. 31, 904–913 (2016).
Houssiau, F. A. Biologic therapy in lupus nephritis. Nephron Clin. Pract. 128, 255–260 (2014).
Moroni, G. et al. Changing patterns in clinical-histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis. Ann. Rheum. Dis. 77, 1318–1325 (2018).
Tektonidou, M. G., Dasgupta, A. & Ward, M. M. Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol. 68, 1432–1441 (2016).
Feldman, C. H. et al. Azathioprine and mycophenolate mofetil adherence patterns and predictors among Medicaid beneficiaries with systemic lupus erythematosus. Arthritis Care Res. 71, 1419–1424 (2018).
Yazdany, J. et al. Quality of care for incident lupus nephritis among medicaid beneficiaries in the United States. Arthritis Care Res. 66, 617–624 (2014).
Davidson, A. What is damaging the kidney in lupus nephritis? Nat. Rev. Rheumatol. 12, 143–153 (2016).
Thacker, S. G. et al. The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J. Immunol. 185, 4457–4469 (2010).
Kahlenberg, J. M. & Kaplan, M. J. The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? Curr. Opin. Rheumatol. 26, 475–481 (2014).
Thanei, S., Vanhecke, D. & Trendelenburg, M. Anti-C1q autoantibodies from systemic lupus erythematosus patients activate the complement system via both the classical and lectin pathways. Clin. Immunol. 160, 180–187 (2015).
Deng, Y. & Tsao, B. P. Updates in lupus genetics. Curr. Rheum. Rep. 19, 68 (2017).
Goulielmos, G. N. et al. The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry. Gene 668, 59–72 (2018).
Friebus-Kardash, J. et al. Susceptibility of BAFF-var allele carriers to severe SLE with occurrence of lupus nephritis. BMC Nephrol. 20, 430 (2019).
Webber, D. et al. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE. Rheumatology 59, 90–98 (2019).
Chung, S. A. et al. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J. Am. Soc. Nephrol. 25, 2859–2870 (2014).
Lanata, C. M. et al. Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients. PLoS One 13, e0199003 (2018).
Canadas-Garre, M. et al. Genetic susceptibility to chronic kidney disease — some more pieces for the heritability puzzle. Front. Genet. 10, 453 (2019).
Wuttke, M. et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat. Genet. 51, 957–972 (2019).
Freedman, B. I. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 66, 390–396 (2014).
Iwamoto, T. & Niewold, T. B. Genetics of human lupus nephritis. Clin. Immunol. 185, 32–39 (2017).
Jourde-Chiche, N. et al. Endothelium structure and function in kidney health and disease. Nat. Rev. Nephrol. 15, 87–108 (2019).
Long, D. A., Norman, J. T. & Fine, L. G. Restoring the renal microvasculature to treat chronic kidney disease. Nat. Rev. Nephrol. 8, 244–250 (2012).
Abboud, H. E. Mesangial cell biology. Exp. Cell Res. 318, 979–985 (2012).
Carlin, L. M. et al. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).
Devarapu, S. K. & Anders, H. J. Toll-like receptors in lupus nephritis. J. Biomed. Sci. 25, 35 (2018).
Sung, S. J. & Fu, S. M. Interactions among glomerulus infiltrating macrophages and intrinsic cells via cytokines in chronic lupus glomerulonephritis. J. Autoimmun. 106, 102331 (2019).
Schlondorff, D. & Banas, B. The mesangial cell revisited: no cell is an island. J. Am. Soc. Nephrol. 20, 1179–1187 (2009).
Bhargava, R. & Tsokos, G. C. The immune podocyte. Curr. Opin. Rheumatol. 31, 167–174 (2019).
El Nahas, M. Kidney remodelling and scarring: the plasticity of cells. Nephrol. Dial. Transpl. 18, 1959–1962 (2003).
Shankland, S. J., Freedman, B. S. & Pippin, J. W. Can podocytes be regenerated in adults? Curr. Opin. Nephrol. Hypertens. 26, 154–164 (2017).
Ferretti, A. P., Bhargava, R., Dahan, S., Tsokos, M. G. & Tsokos, G. C. Calcium/calmodulin kinase IV controls the function of both T cells and kidney resident cells. Front. Immunol. 9, 2113 (2018).
Kello, N. et al. Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: case series and review of literature. Semin. Arthritis Rheum. 49, 74–83 (2018).
Leatherwood, C. et al. Clinical characteristics and renal prognosis associated with interstitial fibrosis and tubular atrophy (IFTA) and vascular injury in lupus nephritis biopsies. Semin. Arthritis Rheum. 49, 396–404 (2019).
Liu, B. C., Tang, T. T., Lv, L. L. & Lan, H. Y. Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int. 93, 568–579 (2018).
Leaf, I. A. et al. Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J. Clin. Invest. 127, 321–334 (2017).
Grgic, I., Duffield, J. S. & Humphreys, B. D. The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr. Nephrol. 27, 183–193 (2012).
Shaw, I., Rider, S., Mullins, J., Hughes, J. & Peault, B. Pericytes in the renal vasculature: roles in health and disease. Nat. Rev. Nephrol. 14, 521–534 (2018).
Lemos, D. R. et al. Interleukin-1β activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 29, 1690–1705 (2018).
Berthier, C. C. et al. Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis. J. Immunol. 189, 988–1001 (2012).
Stamatiades, E. G. et al. Immune monitoring of trans-endothelial transport by kidney-resident macrophages. Cell 166, 991–1003 (2016).
Hsieh, C. et al. Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res. 63, 865–874 (2011).
Ma, R., Jiang, W., Li, Z., Sun, Y. & Wei, Z. Intrarenal macrophage infiltration induced by T cells is associated with podocyte injury in lupus nephritis patients. Lupus 25, 1577–1586 (2016).
Tipping, P. G. & Holdsworth, S. R. T cells in crescentic glomerulonephritis. J. Am. Soc. Nephrol. 17, 1253–1263 (2006).
Bethunaickan, R. et al. A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis. J. Immunol. 186, 4994–5003 (2011).
Schiffer, L. et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J. Immunol. 180, 1938–1947 (2008).
Celhar, T. et al. RNA sensing by conventional dendritic cells is central to the development of lupus nephritis. Proc. Natl Acad. Sci. USA 112, E6195–E6204 (2015).
Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).
Kuriakose, J. et al. Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis. J. Clin. Invest. 130, 2251–2265 (2019).
Sung, S. J. et al. Dependence of glomerulonephritis induction on novel intraglomerular alternatively activated bone marrow-derived macrophages and Mac-1 and PD-L1 in lupus-prone NZM2328 mice. J. Immunol. 198, 2589–2601 (2017).
Hill, G. S., Delahousse, M., Nochy, D., Mandet, C. & Bariety, J. Proteinuria and tubulointerstitial lesions in lupus nephritis. Kidney Int. 60, 1893–1903 (2001).
Hill, G. S. et al. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 59, 304–316 (2001).
Esdaile, J. M., Levinton, C., Federgreen, W., Hayslett, J. P. & Kashgarian, M. The clinical and renal biopsy predictors of long-term outcome in lupus nephritis: a study of 87 patients and review of the literature. Q. J. Med. 72, 779–833 (1989).
Winchester, R. et al. Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell beta-chain clonotypes in progressive lupus nephritis. Arthritis Rheum. 64, 1589–1600 (2012).
Chang, A. et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J. Immunol. 186, 1849–1860 (2011).
Liarski, V. M. et al. Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci. Transl Med. 6, 230ra246 (2014).
Liarski, V. M. et al. Quantifying in situ adaptive immune cell cognate interactions in humans. Nat. Immunol. 20, 503–513 (2019).
Kassianos, A. J. et al. Increased tubulointerstitial recruitment of human CD141hi CLEC9A+ and CD1c+ myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease. Am. J. Physiol. Renal Physiol. 305, F1391–F1401 (2013).
Kinloch, A. J. et al. Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol. 66, 3359–3370 (2014).
Divanyan, T., Acosta, E., Patel, D., Constantino, D. & Lopez-Soler, R. I. Anti-vimentin antibodies in transplant and disease. Hum. Immunol. 80, 602–607 (2019).
Caputa, G., Castoldi, A. & Pearce, E. J. Metabolic adaptations of tissue-resident immune cells. Nat. Immunol. 20, 793–801 (2019).
Tang, P. M., Nikolic-Paterson, D. J. & Lan, H. Y. Macrophages: versatile players in renal inflammation and fibrosis. Nat. Rev. Nephrol. 15, 144–158 (2019).
Sahu, R., Bethunaickan, R., Singh, S. & Davidson, A. Structure and function of renal macrophages and dendritic cells from lupus-prone mice. Arthritis Rheumatol. 66, 1596–1607 (2014).
Maria, N. I. & Davidson, A. Renal macrophages and dendritic cells in SLE nephritis. Curr. Rheumatol. Rep. 19, 81 (2017).
Bajema, I. M. et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int. 93, 789–796 (2018).
Malvar, A. et al. Histologic versus clinical remission in proliferative lupus nephritis. Nephrol. Dial. Transpl. 32, 1338–1344 (2017).
De Rosa, M. et al. A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy. Kidney Int. 94, 788–794 (2018).
Mackay, M. et al. Establishing surrogate kidney end points for lupus nephritis clinical trials: development and validation of a novel approach to predict future kidney outcomes. Arthritis Rheumatol. 71, 411–419 (2018).
Tamirou, F. et al. A proteinuria cut-off level of 0.7g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Sci. Med. 2, e000123 (2015).
Brunner, H. I. et al. Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus. Pediatr. Nephrol. 34, 117–128 (2019).
Stanley, S. et al. Identification of low-abundance urinary biomarkers in lupus nephritis using electrochemiluminescence immunoassays. Arthritis Rheumatol. 71, 744–755 (2019).
Anania, V. G. et al. Discovery and qualification of candidate urinary biomarkers of disease activity in lupus nephritis. J. Proteome Res. 18, 1264–1277 (2018).
Hayek, S. S. et al. Cardiovascular disease biomarkers and suPAR in predicting decline in renal function: a prospective cohort study. Kidney Int. Rep. 2, 425–432 (2017).
Ju, W. et al. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci. Transl Med. 7, 316ra193 (2015).
Hoover, P. et al. The Accelerating Medicines Partnership: organizational structure and preliminary data from the phase 1 studies of lupus nephritis. Arthritis Care Res. 72, 233–242 (2020).
Toro-Dominguez, D. et al. Stratification of systemic lupus erythematosus patients into three groups of disease activity progression according to longitudinal gene expression. Arthritis Rheumatol. 70, 2025–2035 (2018).
Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 551–565 (2016).
Chaussabel, D. et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29, 150–164 (2008).
Chiche, L. et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol. 66, 1583–1595 (2014).
Jourde-Chiche, N. et al. Modular transcriptional repertoire analyses identify a blood neutrophil signature as a candidate biomarker for lupus nephritis. Rheumatology 56, 477–487 (2017).
Wither, J. E. et al. Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: clinical/pathologic associations and etiologic mechanisms. PLoS One 13, e0196117 (2018).
Toro-Dominguez, D. et al. Differential treatments based on drug-induced gene expression signatures and longitudinal systemic lupus erythematosus stratification. Sci. Rep. 9, 15502 (2019).
Panousis, N. I. et al. Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Ann. Rheum. Dis. 78, 1079–1089 (2019).
Lyons, P. A. et al. Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis. Ann. Rheum. Dis. 69, 1208–1213 (2010).
McKinney, E. F. & Smith, K. G. T-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. Immunol. Cell Biol. 94, 935–942 (2016).
Lanata, C. M., Chung, S. A. & Criswell, L. A. DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity. Lupus Sci. Med. 5, e000285 (2018).
Breitbach, M. E., Ramaker, R. C., Roberts, K., Kimberly, R. P. & Absher, D. Population-specific patterns of epigenetic defects in the B cell lineage in patients with systemic lupus erythematosus. Arthritis Rheumatol. 72, 282–291 (2020).
Hedrich, C. M. Epigenetics in SLE. Curr. Rheumatol. Rep. 19, 58 (2017).
Chen, S. et al. Genome-wide DNA methylation profiles reveal common epigenetic patterns of interferon-related genes in multiple autoimmune diseases. Front. Genet. 10, 223 (2019).
Richardson, B. Epigenetically altered T cells contribute to lupus flares. Cell 8, E127 (2019).
Li, H. et al. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI Insight 3, 120880 (2018).
Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).
Lyu, Z. et al. PPARγ maintains the metabolic heterogeneity and homeostasis of renal tubules. EBioMedicine 38, 178–190 (2018).
Gomez, I. G., Nakagawa, N. & Duffield, J. S. MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am. J. Physiol. Renal Physiol. 310, F931-F944 (2016).
Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).
Gu, X., Raman, A. & Susztak, K. Going from acute to chronic kidney injury with FoxO3. J. Clin. Invest. 129, 2192–2194 (2019).
Li, L. et al. FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J. Clin. Invest. 130, 2374–2389 (2019).
Bethunaickan, R. et al. Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice. Arthritis Rheumatol. 66, 2246–2258 (2014).
Zuk, A. & Bonventre, J. V. Recent advances in acute kidney injury and its consequences and impact on chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 28, 397–405 (2019).
Papalexi, E. & Satija, R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat. Rev. Immunol. 18, 35–45 (2018).
Der, E. et al. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat. Immunol. 20, 915–927 (2019).
Yoshimoto, S. et al. Elevated levels of fractalkine expression and accumulation of CD16+ monocytes in glomeruli of active lupus nephritis. Am. J. Kidney Dis. 50, 47–58 (2007).
Cros, J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33, 375–386 (2010).
Dall’Era, M. et al. Current challenges in the development of new treatments for lupus. Ann. Rheum. Dis. 78, 729–735 (2019).
Murphy, G. & Isenberg, D. A. New therapies for systemic lupus erythematosus—past imperfect, future tense. Nat. Rev. Rheumatol. 15, 403–412 (2019).
Ayoub, I., Nelson, J. & Rovin, B. H. Induction therapy for lupus nephritis: the highlights. Curr. Rheumatol. Rep. 20, 60 (2018).
GlaxoSmithKline. GSK announces positive headline results in phase 3 study of Benlysta in patients with lupus nephritis. gsk.com https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-headline-results-in-phase-3-study-of-benlysta-in-patients-with-lupus-nephritis/ (2019).
van Vollenhoven, R. F. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392, 1330–1339 (2018).
Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).
Furie, R. A. et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 1, 208–219 (2019).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02547922 (2020).
Park, D. J. et al. Efficacy and safety of mycophenolate mofetil and tacrolimus combination therapy in patients with lupus nephritis: a nationwide multicentre study. Clin. Exp. Rheumatol. 37, 89–96 (2019).
Zhou, T., Lin, S., Yang, S. & Lin, W. Efficacy and safety of tacrolimus in induction therapy of patients with lupus nephritis. Drug Des. Devel. Ther. 13, 857–869 (2019).
Sin, F. E. & Isenberg, D. An evaluation of voclosporin for the treatment of lupus nephritis. Expert Opin. Pharmacother. 19, 1613–1621 (2018).
Rovin, B. H. et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 95, 219–231 (2019).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03021499 (2019).
Roche. FDA grants breakthrough therapy designation for Roche’s Gazyva (obinutuzumab) in lupus nephritis. Roche.com https://www.roche.com/media/releases/med-cor-2019-09-18.htm (2019).
Furie, R. et al. A phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of obinutuzumab or placebo in combination with mycophenolate mofetil in patients with active class III or IV lupus nephritis [abstract]. Arthritis Rheumatol. 71, 939 (2019).
Canaud, G. et al. Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair. Sci. Transl Med. 11, eaav4754 (2019).
Yang, B. et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J. Am. Soc. Nephrol. 29, 1900–1916 (2018).
Rauchman, M. & Griggs, D. Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis. Transl Res. 209, 90–104 (2019).
Liu, F. et al. Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease. Clin. Sci. 131, 2125–2143 (2017).
Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019).
Liu, Y. & Kaplan, M. J. Cardiovascular disease in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 30, 441–448 (2018).
Fried, L. F. et al. Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J. Am. Coll. Cardiol. 41, 1364–1372 (2003).
Gansevoort, R. T. et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 80, 93–104 (2011).
Schmidt, T. et al. Function of the Th17/interleukin-17A immune response in murine lupus nephritis. Arthritis Rheumatol. 67, 475–487 (2015).
Wada, Y. et al. IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis in MRL-Faslpr mice. J. Am. Soc. Nephrol. 30, 244–259 (2019).
Perper, S. J. et al. Treatment with a CD40 antagonist antibody reverses severe proteinuria and loss of saliva production and restores glomerular morphology in murine systemic lupus erythematosus. J. Immunol. 203, 58–75 (2019).
Furumoto, Y. et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. 69, 148–160 (2017).
Kitai, M. et al. Effects of a spleen tyrosine kinase inhibitor on progression of the lupus nephritis in mice. J. Pharmacol. Sci. 134, 29–36 (2017).
Ma, T. K., McAdoo, S. P. & Tam, F. W. Targeting the tyrosine kinase signalling pathways for treatment of immune-mediated glomerulonephritis: from bench to bedside and beyond. Nephrol. Dial. Transpl. 32, i129-i138 (2017).
Bahjat, F. R. et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum. 58, 1433–1444 (2008).
Katewa, A. et al. BTK-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell-associated damage in IFNα-driven lupus nephritis. JCI Insight 2, e90111 (2017).
Chalmers, S. A. et al. BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis. Clin. Immunol. 197, 205–218 (2018).
Qing, X. et al. iRhom2 promotes lupus nephritis through TNF-alpha and EGFR signaling. J. Clin. Invest. 128, 1397–1412 (2018).
Lech, M. et al. NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. Ann. Rheum. Dis. 74, 2224–2235 (2014).
Fu, R. et al. Pim-1 as a therapeutic target in lupus nephritis. Arthritis Rheumatol. 71, 1308–1318 (2019).
Peng, X. et al. Piperine ameliorated lupus nephritis by targeting AMPK-mediated activation of NLRP3 inflammasome. Int. Immunopharmacol. 65, 448–457 (2018).
Yang, J., Yang, X., Yang, J. & Li, M. Baicalin ameliorates lupus autoimmunity by inhibiting differentiation of Tfh cells and inducing expansion of Tfr cells. Cell Death Dis. 10, 140 (2019).
Qi, Y. Y. et al. Increased autophagy is cytoprotective against podocyte injury induced by antibody and interferon-alpha in lupus nephritis. Ann. Rheum. Dis. 77, 1799–1809 (2018).
Zhang, C. et al. Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis. Clin. Sci. 133, 1721–1744 (2019).
Liang, C. L. et al. Mangiferin attenuates murine lupus nephritis by inducing CD4+Foxp3+ regulatory T cells via suppression of mTOR signaling. Cell Physiol. Biochem. 50, 1560–1573 (2018).
Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl Med. 7, 274ra218 (2015).
Maeda, K. et al. CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. J. Clin. Invest. 128, 3445–3459 (2018).
Pham, G. S., Wang, L. A. & Mathis, K. W. Pharmacological potentiation of the efferent vagus nerve attenuates blood pressure and renal injury in a murine model of systemic lupus erythematosus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315, R1261–R1271 (2018).
Lee, H. K. et al. CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms. Sci. Rep. 7, 41258 (2017).
Perico, N., Casiraghi, F. & Remuzzi, G. Clinical translation of mesenchymal stromal cell therapies in nephrology. J. Am. Soc. Nephrol. 29, 362–375 (2018).
Sattwika, P. D., Mustafa, R., Paramaiswari, A. & Herningtyas, E. H. Stem cells for lupus nephritis: a concise review of current knowledge. Lupus 27, 1881–1897 (2018).
Liu, S., Guo, Y. L., Yang, J. Y., Wang, W. & Xu, J. Efficacy of mesenchymal stem cells on systemic lupus erythematosus: a meta-analysis. Beijing Da Xue Xue Bao Yi Xue Ban. 50, 1014–1021 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03580291 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03597464 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03610516 (2020).
Albach, F. N. et al. Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases. Eur. J. Clin. Pharmacol. 74, 161–169 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03385564 (2020).
Furie, R. et al. FRI0196 treatment of systemic lupus erythematosus patients with the immunoproteasome inhibitor KZR-616: results from the first 2 cohorts of an open-label phase 1b dose escalation trial. Ann. Rheum. Dis. 78, 776–777 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03393013 (2020).
Robak, T. GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies. Curr. Opin. Investig. Drugs 10, 588–596 (2009).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04221477 (2020).
Burke, J. R. et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci. Transl Med. 11, eaaw1736 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03943147 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02547922 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01639339 (2019).
Takeuchi, T., Okada, K., Yoshida, H. & Yagi, N. Post-marketing surveillance study of the long-term use of mizoribine for the treatment of lupus nephritis: 2-year results. Mod. Rheumatol. 28, 85–94 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02256150 (2019).
Yan, Q. et al. Prevention of immune nephritis by the small molecular weight immunomodulator iguratimod in MRL/lpr mice. PLoS One 9, e108273 (2014).
Yan, Q., Bao, C., Kang, Y., Fu, Q. & Wang, R. Iguratimod is an alternative option for refractory lupus nephritis: a preliminary observational study [abstract]. Arthritis Rheumatol. 71, 2568 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02936375 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04181762 (2019).
The work of the authors was funded by The Lupus Research Alliance, the US National Institutes of Health (grant RO1 AR064811–01 to A.D.) and the US Department of Defense (grant W81XWH-17–1–0657 to A.D.).
References were selected using Medline search and the terms ‘lupus’ and/or ‘nephritis’ with ‘therapies’, ‘inflammation’, ‘endothelial cells’, ‘podocytes’, ‘biomarkers’, ‘macrophages’, ‘dendritic cells’, ‘T cells’, ‘B cells’, ‘cytokines’, ‘fibrosis’ and ‘renal tubules’. Articles published between 2016 and 2019 were given preference for inclusion. In addition, a personal collection of articles was used that includes ~5,000 references related to SLE and novel therapies.
The authors declare no competing interests.
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Nature Reviews Rheumatology thanks G. Gilkeson, R. Misra and F. Yu for their contribution to the peer review of this work.
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- Capillary rarefaction
A loss of capillary structure leading to reduced density of microvascular networks.
- Glomerular crescents
A response to severe injury in which crescent-shaped glomerular lesions that consist of epithelial cells, fibroblasts, immune cells and matrix form adjacent to the Bowman’s capsule.
- Foot process effacement
A podocyte reaction to injury or damage in which the epithelial foot processes become flattened and lose their barrier function, resulting in proteinuria.
- Glomerular tuft
A network of small blood vessels and supporting cells that forms the initial structural component of the nephron.
Scarring of the glomeruli that leads to loss of function.
- Fate mapping
A technique used in developmental biology to study the embryonic origin of adult cells, tissues and structures.
- Exhaustion signature
A cell state or phenotype with progressive loss of effector cytokine or cytotoxic function owing to prolonged antigen stimulation, often characterized by the increased expression of immune checkpoint inhibitory receptors, alterations in metabolic function and a distinct transcriptional profile that differs from that of anergic cells.
The use of multiple medications to treat complex medical conditions.
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Maria, N.I., Davidson, A. Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy. Nat Rev Rheumatol 16, 255–267 (2020). https://doi.org/10.1038/s41584-020-0401-9
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